1. Field of the Invention
The present invention is directed to an improved method of making cyclopentyl 2-thienyl ketone, tiletamine and tiletamine acid addition salts, such as tiletamine hydrochloride.
2. Description of the Prior Art
U.S. Pat. No. 3,522,273 ('273) discloses a method of making tiletamine, or 2-amino-2-(2-thienyl)cyclohexanone, and tiletamine acid addition salts, such as the hydrochloride.
As disclosed in the '273 patent, there are two routes to the synthesis of tiletamine hydrochloride, based on cyclopentyl 2-thienyl ketone (Scheme 1) or tetrahydro-2-pyranyl ether of cyclopentanone cyanohydrin (Scheme 2) as starting compounds, as follows: ##STR1##
Due to availability of the starting compound, lower number of separate steps, lower raw material and operational costs, Scheme 1 is more promising than Scheme 2. However, both Schemes have several shortcomings. First, each step of the synthesis requires a different solvent. Multiple solvents complicate the post-reaction work-up, isolation and solvent recovery steps, and add significantly to the manufacturing cost of the process. In addition, solvents such as carbon tetrachloride and ether are restricted solvents. Moreover, ether is difficult to recover industrially and highly flammable. Second, the processes typically call for multiple isolations and purifications of the intermediates, which substantially affects the operational cost of commercial manufacture.
Cyclopentyl 2-thienyl ketone has been prepared by the Friedel-Crafts reaction of thiophene with initially pre-formed cyclopentanecarboxylic acid chloride (Scheme 3), as disclosed in U.S. Pat. No. 5,597,832 or with tetracyclopentylcarboxysilane (Scheme 4), Jur'ew, Yu K., et al. Zh. Obshch-Khim., 26, 1956 3341-3344: ##STR2##
Both Schemes 3 and 4 have the same major shortcoming-stannic chloride is used as a catalyst for the Friedel-Crafts reaction. In addition to its cost, stannic chloride introduces a heavy metal contamination to the process waste stream which is a major problem during manufacture.
It is also known, that cyclopentyl 2-thienyl ketone can be prepared from N'-tosylcyclopentylamidine by reaction with 2-thienyl lithium (Scheme 5), see Clerici, F. et al. Synthesis, 11, 1987, 1025-1027: ##STR3##
This Scheme 5 approach has some scientific interest, but is not desirable from a commercial production standpoint.
In accordance with the present invention, we have discovered alternatives to the original acylation routes to synthesize cyclopentyl 2-thienyl ketone. It has been found that cyclopentanecarboxylic acid can be directly reacted with thiophene, without first forming the cyclopentanecarboxylic acid chloride, using a water scavenging solvent, such as polyphosphoric acid, at unexpectedly high yields, to avoid the stannic chloride (heavy metal) waste stream contamination. In accordance with a preferred embodiment of the present invention, polyphosphoric acid is the water scavenging solvent of choice for the Friedel-Crafts reaction of cyclopentanecarboxylic acid and thiophene (Scheme 6).
As shown in the prior art method of Scheme 3, the prior art reaction requires first forming the acid chloride, requires a tin-containing catalyst, such as a stannic chloride, and methylene chloride as a solvent for the reaction of cyclopentanecarboxylic acid chloride with thiophene to form cyclopentyl 2-thienyl ketone. In accordance with the present invention, the synthesis of cyclopentyl 2-thienyl ketone, in accordance with the following reaction, can be achieved by directly reacting cyclopentanecarboxylic acid with thiophene in polyphosphoric acid. ##STR4##
In comparison with published procedures for the preparation of cyclopentyl 2-thienyl ketone, this approach has the following advantages:
1. This route is the most direct and bypasses the formation of the acid chloride, PA1 2. Polyphosphoric acid plays role both a solvent and a reagent, which is a water scavenger, and PA1 3. It eliminates the need to use thionyl chloride (a reagent for acid chloride formation) or tetrachlorosilane (for a synthesis of organosilyl derivative) and stannic chloride (a catalyst for the Friedel-Crafts reaction). PA1 1. Tiletamine and its hydrochloride salt are produced with high yield. PA1 2. The multi-solvent process can be replaced by a procedure, employing only one solvent for the synthesis of tiletamine free base from cyclopentyl 2-thienyl ketone--two solvents for good yields of tiletamine acid addition salts, involving a second solvent only at the acid addition salt step of the process. PA1 3. A crude reaction mixture can be carried through five steps while avoiding complicated work ups, isolations, and purifications of the intermediates.
As disclosed in Snyder, Elston, J. Amer. Chem Soc: 77, 1955, 364, polyphosphoric acid was used in a reaction of thiophene and acetic acid, using about 5 times more polyphosphoric acid than the amount found effective in accordance with the present invention. To achieve the full advantage of the present invention, the above Scheme 6 reaction is carried out using a weight ratio of water-scavenging solvent, e.g., polyphosphoric acid, to thiophene of less than about 10:1, preferably less than about 8:1, more preferably less than about 5:1, and most preferably less than about 2.3:1 to avoid or lessen polyphosphoric acid waste water disposal problems (see Minai, et al. U.S. Pat. No. 5,235,068) while providing unexpected yields. To achieve the full advantage of the present invention, the weight ratio of water-scavenging solvent, e.g., polyphosphoric acid, to thiophene should be at least 1:1, preferably at least 1.5:1, more preferably at least 2:1.
In accordance with the preferred embodiment of the above reaction, a three component mixture was stirred at 75.degree. C. for 2 hours. Then, the reaction mixture was diluted with water and extracted with o-dichlorobenzene to afford 99% pure product (GC, area % analysis). The mixture was azeotropically dried by stripping a small portion of the solvent. The crude mixture was submitted to the next step (Scheme 7). Halogenation (bromination) of the crude cyclopentyl 2-thienyl ketone at room temperature (Scheme 7) gave the corresponding .alpha.-halogenated ketone with a high purity, usually 97-99% by GC, area % analysis. ##STR5##
A work up procedure after the bromination step is a simple evaporation of the solvent, which can be collected and recycled to any step of the process. Evaporation of the o-dichlorobenzene removes residual hydrogen bromide as well. A crude material, without any purification, was carried through directly to the next amination step. A 75% wt/wt solution of .alpha.-bromoketone in o-dichlorobenzene was used to prevent solidification of the starting material during amine addition. The amination reaction resulted in 96% pure (GC, area % analysis) product (Scheme 8). ##STR6##
An excess of ethylamine, used in the reaction, was evaporated from the reaction mixture under mild vacuum, and the ethylamine was recovered and recycled. An ethylamine hydrobromide salt by-product was washed out with water. A solution of crude 1-hydroxycyclopentyl 2'-thienyl N-ethyl ketimine in o-dichlorobenzene was refluxed for 1.5 hours at a temperature of at least about 100.degree. C., preferably about 180.degree. C. to about 230.degree. C., e.g. 220.degree. C. to 225.degree. C., to produce 90% pure (GC, area % analysis) tiletamine free base by the thermal rearrangement reaction shown in Scheme 9. ##STR7##
The single solvent strategy, after formation of cyclopentyl 2-thienyl ketone, as shown in Schemes 7, 8 and 9, and the capability of transferring a crude reaction mixture through all steps 6, 7, 8 and 9, without isolation of the intermediates resulted in up to 70% yield (based on cyclopentanecarboxylic acid) of tiletamine free base. The conversion of tiletamine to its hydrochloride salt in o-dichlorobenzene at this stage allows for the use of only a single solvent throughout the entire process. However, a reaction of hydrogen chloride gas with tiletamine in o-dichlorobenzene was found to result in conversion of only about 39% of the available free base to the hydrochloride salt. Therefore, a different solvent was used for the final step. In the prior art method diethyl ether was the solvent of choice for this step, but diethyl ether is flammable and very difficult to handle. We have found that the use of di-n-butyl ether or t-butyl methyl ether and HCl gas result in the complete conversion of tiletamine to the corresponding hydrochloride salt, as shown in the acid addition salt reaction of Scheme 10. ##STR8##
The above-described synthesis of cyclopentyl 2-thienyl ketone, tiletamine and tiletamine acid addition salts has the following distinct advantages: